IE49409B1

IE49409B1 - Azetidinone derivatives

Info

Publication number: IE49409B1
Application number: IE2340/84A
Authority: IE
Original assignee: Erba Farmitalia
Priority date: 1979-02-24
Filing date: 1980-02-20
Publication date: 1985-10-02
Also published as: IE49408B1; IE842339L; IE49410B1; IE842340L; IE842341L

Description

The invention relates to processes for the preparation 5 of azetidinone derivatives and to certain of the azetidinone derivatives.

More particularly the invention relates to azetidinone derivatives of the general formula 1 wherein R' represents a hydrogen atom or an alkyl, alkoxy, or hydroxyaikyl group, each of which has from 1 to 4 carbon atoms, the alcoholic function of the hydroxyaikyl group being free or protected by a p. nitrobenzyloxycarbonyl group; and X represents a group of the formula CHgZ or CH^Z1 wherein Z representsa hydroxy, amino or carbamoyloxy group, or a group of the formula OR^ or OCOR^ wherein R^ represents an alkyl group having from 1 to 4 carbon atoms and Z’ represents a mercapto or pyridinium group, or a 20 group of the formula SRg wherein R3 represents an alkyl group having from 1 to 4 carbon atoms or a 5-methyl-l,3, 4-thiadiazol-2-yl, l-methyl-lH-tetrazol-5-yl, 1,2,3,-triazol-5-yl or pyrazinyl group. The 3-substituent may have the a- or β-configuration. 3o-substitution is preferred. - 3 The invention provides a process for the preparation of compounds of the general formula I in which R' is as above defined and X represents a group of the formula CHgZ wherein Z is as above defined. The process is 5 illustrated by the following reaction scheme, in which R' is as above defined, R represents an alkyl group and Y represents a hydrogen atom, a lower alkyl, cyano or alkoxycarbonyl group or a group of the formula CHgZ in which Z is as above defined. 494 09 (13) 48409 - 5 The process comprises condensing, in an inert solvent at elevated temperature, a penicillanic acid S-oxide ester of the general formula (2) with an acetylenic compound of the general formula TCHjCaCY, isanerising the resultant caipound of the general formula (3), preferably in basic conditions, reducing the 4£-(substituted vinylsulphinyl) group of the resultant azetidinone derivative of the general formula (4) by the action of a reducing agent, submitting the resultant azetidinone derivative of the general formula (12) to ozonolysis in solution at reduced temperature whereby both carbon-carbon double bonds are converted to keto groups, and removing the 1-alkoxyoxalyl group from the resultant azetidinone derivative of the general formula (13) by mild alkaline hydrolysis or by the action of silica gel.

The preparation of compounds of the general formula I in which R' is as herein defined and X represents a group of the formula CHjZ' in which 2' is as herein defined is carried out according to the above process with the additional step of converting the substituent 2 into a substituent of the formula 2'. The additional step may be carried out at any stage in the above process after the condensation of the penicillanic acid S-oxide ester (2) with the acetylenic ccnpound ZCH^CaCY and is necessary because of the difficulty of condensing the penicillanic acid S-oxide ester (2) directly with an acetylenic compound HSCHg-OCY, R^SCHj-CsCY or PyCHj-CSSY in which Py represents a - 49*09 - 6 pyridinium ion. This process is also within the scope of the invention.

The reduction of the azetidinone derivative (4) may be carried out using phosphorus tribromide or sodium iodide in acetyl chloride as reducing agent.

'.'Tien R' represents a hydroxyalkyl group in the desired compound of the general formula I» the reaction sequence is preferably carried out with the alcoholic function protected.

The starting materials of the general formula (2) in which R' represents a hydrogen atom may be prepared from (5R)~ -6-aminopenicillanic acid following known procedures (see Cignarella et al.. Journal of Organic Chemistry, 27, 2668 and EVRARD et al., Nature, 201, 1124). .15 When R' represents a ci-c4 alkyl or hydroxyalkyl nroup, it can be introduced according to the procedure of Di Ninno et al., Journal of Organic Chemistry 42, 2960 (1977). When R' represents a C^-C^ alkoxy group, it may be introduced according to the procedures of Hauser et al., Helv. Chem.

Acta, 50, 1327 (1967) and Giddings et al.. Tetrahedron Letters, Il, 995, (1978). Alternatively compounds of general formula (2) in which R' represents a hydrogen atom can be converted to compounds of the general formula (2) in which R' represents a C^-C^ alkyl or hydroxyalkyl group - 7 by introducing the substituent into the 6-position using a strong base, as illustrated in the following Examples. Compounds of the general formula (2) in which R' represents a C^-C^ alkyl or hydroxyalkyl group can also be prepared starting from a suitable ester of penicillanic acid S-oxide, as illustrated in the following Examples. The substitution at the 3-position is stereospecifically directed to the 3O.-derivatives.

The compounds of the general formula I as above defined are useful as intermediates in the preparation of certain penem-carboxylic acids and esters which have a wide spectrum of antibacterial activity as well as a p-lactamase inhibiting activity (see specification of Application No. 338/80, from which this Application is divided). It should be pointed out that the stereochemistry at C^ of the compounds according to the invention, as well as that of all the intermediates of their preparation, is the same as in naturally occurring penicillins and cephalosporins.

Certain of the compounds of the general formula I as above defined themselves form part of the invention. They are those in which X represents a group of the formula CH^A in which A represents a carbamoyloxy or pyridinium group or a group of the formula OCORj - 8 or SR^ wherein Rj and are as above defined and R' represents a hydroxyalkyl group having from 1 to 4 carbon atoms, the alcoholic function of the hydroxyalkyl group being free or protected by a p-nitro5 benzyloxycarbonyl group. Preferably R' represents a 1-hydroxyethyl or 1-(p-nitrobenzyloxycarbonyloxy)-ethyl group. i 49408 - 9 The following Examples illustrate the invention.

EXAMPLE 1 4β-(l-acetoxymethy1-3-acetoxy-l-propeny1sulphlny1)-1- (l-methoxycarbony1-2-methyl-ally1) -'azetidin-'2-one (3): R=CH3; R'=H, Y=CH2O.CO.CH3, Z=0C0CH3 A solution of 2.0 g of methyl penicillinate S-oxide and 2.8 g of butyndiol diacetate in 40 ml of toluene was refluxed for 24 hours. 1.4 g of the title compound was obtained after purification by column chromatography on silica gel eluting with 96:4 by volume dichloromethane:ethyl acetate.

PMR (CDC13) · 2.03 δ (s, CHg-C-), 2.15 and 2.20 g (two s, 2 CH3CO), 2.88 δ (dd, Jgex = 14Hz, Jvic cis = 4 Hz, C-3-Ηα) t 3.38 δ (dd, J gem = 14Hz, Jvic trans = 2Hz, C-3-H5) 9 3.83 δ (S, ch30), 4.88 δ (<3, Jvic = 6Hz, CH--C-) * 1 (H) 4.92 δ (broad s, CH2~C= b ι « -N C 4.93-5.33 6 (m, =¾ and ) COO .32 6 (dd, Jvic = 4 and 2Hz, C-4-H) , 6.47 δ (t, Jvic = 6Hz, =C-C(H2)) vt - 10 EXAMPLE 2 g-(1-acetoxymethy1-3-acetoxy-l-propenylsulphinyl)-1- (l-methoxycarbonyl-2-methyl-l-propenyl) -azetidin-2-one (4): R=CH3, R’=H, Y=CH2O.CO.CH3 , Z=QCOCH3 1.7 g of the compound prepared in Example 1 were dissolved in 80 ml of dichloromethane. 0.5 ml of triethylamine were added and the solution was left for a few hours at room temperature. After evaporating off the solvent, the title compound was obtained in pure form in quantitative yield.

PMR (CDC13) : 2.14 (9H) and 2.32 (3H) δ (two s, 2 CH3C0 and 2 CH3-C=), 2.92 δ (dd, Jgem=15Hz, Jvic cis =5Hz, C-3-HQ), 3.38 δ (dd, Joem=15Hz, Jvic trans = 2.5Hz, C-3-Ηβ), 3.82 δ (s, CH30) 4.88 δ (d, Jvic=6.5Hz, CH2-C=, 4.92 δ (s, (H) CH2-C=), 5.15 δ (dd, Jvic=5 and 2.5Hz, C-4-H), 6.50 δ (t, Jvic 6.5Hz, =C- (H-j)) H EXAMPLE 3 20-4 B-acetylglycolloylthio-l-acetoxymethoxyoxalyl-azetidin-2-one. (13): R= CH2O.CO.CH3, R'=H , X=0.C0.CH3 0.8 g of 48-(1-acetoxymethy1-3-acetoxy-l-propenylthio)-125 -(l-acetoxymethoxycarbonyl-2-methyl-l-propenyl)-azetidin-2-one were dissolved in 80 ml of dichloromethane and cooled to -78°C. A flow of ozone in oxygen was bubbled - 11 through the solution until a blue colour appeared. The solution, after shaking with an aqueous solution of sodium pyrosulphite, was dried over anhydrous sodium sulphate.

The solvent was removed by evaporation to give 0.45 g of the title compound.

PMR (CDC13) : 2.10 and 2.13 6 (two s, 2CH3CO), 3.20 δ (dd, Jgem= 17Hz, Jvic trans = 3.5Hz, C-3-Ηβ), 3.77 δ (dd, Jgem=17Hz, Jvic cis=5.5Hz, C-3-Ha) 4.73 δ (s, -CO-CH2-OCO-), 5.73 δ (dd, Jvic= 10 5.5 and 3.5Hz, C-4-H), 5.87 δ (s, COO-CHj-OCO) EXAMPLE 4 4E-acetylglycolloylth3o-azetidin-2-one (14): R'=H, Z=O.CO.CH3 0.6 g of 4S-acetylglycolloylthio-l-methoxyoxalyl-azetidin15 -2-one were dissolved in'100 ml of methanol and a few grams of silica gel were added under stirring. After one hour the silica gel was filtered off and the resulting solution gave, after evaporation of the solvent therefrom, 0.35 g of the title compound.

PMR (CDClg) : 2,20 δ (s, CHgCO), 3.03δ (cd, Jqem =16Hz, Jvic trans=2.5Hz, C-3-H6), 3.50 δ (dd, Jgem= 16Hz, Jvic cis=4.5Hz, C-3-Hs ) , 4.77 δ (s, -CO-CH2-OCO-), 5.32 « (dd, Jvic=4.5 and 2.5Hz, C-4-H), 6.40 { (broad s, ΚΞ). - 12 EXAMPLE 5 4g- (l-hydroxymethyl-vlnylsulphinyl)-1-(l-methoxycarbonyl-2-methyl-allyl)-azetidin-2-one. (3): R=CH3, R’=Y=H, ?.=OH 4 g of methyl penicillanate S-oxide were dissolved in 15 ml of toluene and refluxed with 15 ml of propargyl alcohol for 8 hours. After evaporating off the solvent in vacuo, the residue was purified by short column chromatography on silica gel, eluting with dichloromethane:ethyl acetate (1:1 by volume]. 2.8 g of the title compound were obtained.

PMR (CDC13)δ :1.96 (bs, 3 H, C-CH3); 2.91 and 3.35 (dd, 2H, J=2Hz, 5Hz, 15Hz, CO-CH2-CH-S); 3.78 (s, 3 H CCCCH3)j 4.36 (bs, 2 H, CH70H); 4.90-5.25 (m, 3 H, CH-C00CH3, C-C=CH2); 5.35 (m, 1 H, CE--CH-S)ί 5.88 (s, 2 H, CH2=C-S).

EXAMPLE 6 8-(1-hydroxymethyl-vlnylsulphinyl)-l-(l-methoxycarbonyl-2-methyl-l-propenyl)-azetidin-2-one (4): R=CH3, R'=Y=H, Z=OH 3.0 g of the compound prepared in Example 5 were dissolved in 100 ml of di chloromethane and left at room temperature for a few hours. After evaporating the solvent from the solution, the residue consisted of the title compound in pure form. Quantitative yield.

PMR (CDC13) δ :1.38 (s, 3 H, =C-CH3); 2.18 (s, 3 H, =C-CH3); 2.~-3.6 (m, J=2Hz, 16Hz, C0-CH7-CH-S); - 13 3.78 (s, 3 H, C00CH3); 4.35 (s, 2 H, CHjOH); .32 (m, 1 H, CH-S) ; 5.90 (bs, 2 H, =¾) · EXAMPLE 7 6-(l-bromomethyl-vinylthio)-1-(l-methoxycarbonyl-2-methyl -1-propenyl)-azetidln-2-one. (12): R=CH3, R'=Y=H, Z=Br 1.8 σ of the compound prepared in Example 5 were dissolved in 40 ml of dimethylformamide and cooled to -20°C. 0.7 ml of pyridine and 3.0 ml of phosphorus tribromide were added and the mixture was left for 15minutes under stirring. Ethyl acetate was added and the organic layer was shaken with a saturated solution of sodium bicarbonate;' washed with water and then dried over anhydrous sodium sulphate to give, after evaporating off the solvent, 1.6 g of the title compound.

CH PMR (CDC1,) δ :2.04 (s, 3 H, 7 3)· 2.24 (s, 3 H ); 3 CH 3.24 (dd, J=2.8, 5, 16Hz, 2 H, 3 C-CHj-CH) ; 3.75 (s, 3 H, 0¾) ; 4.02 (s, 2 H, CH2Br); 5.24 (bs, 1 H, =CH); 5.37 (dd, J=2.8Hz, 5Hz, 1 H, CHj-CH-S); 5.60 (bs, 1 H, =CH).

EXAMPLE 8 4β-/1- (1-me thy l-lH-tetrazol-5-yl-thiome thyl) -vinylthio7-l-(l-methoxycarbonyl-2-methyl-l-propenyl)-azetldln-2-one - 14 (12): R=CH3, R'=Y=H, 1.4 σ of the compound prepared in Example 7 were dissolved in 25 ifal of tetrahydrofuran and cooled to O°C. 0.8 g of l-methyl-5-wercapto-tetrazole sodium salt were added and the mixture was left under stirring for three hours at room temperature. After filtering off the insoluble matter, the mixture was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulphate and evaporated to dryness. The residue consisted of 2.0 g of the title compound in pure form.

PMR (CDC13) 6 :2.00 (s, 3 H, = C-CHj)ϊ 2.22 (s, 3 H, =C-CH3) 2.70-3.80 (m,.2 H, J=2Hz, 5Hz, 15Hz, CO-CH2~ -CH-S) ; 3.72 (s, 3 H, COOCH-j); 3.95 (s, 3 H, N-CH3); 4.10 (s, 2 H, CH-j-S) ; 5.18 (bs, 1 H, S-C=CH); 5.36 (m, 1 H, CHj-CH-S); 5.57 (bs, H, S-C=C-H).

EXAMPLE 9 (l-methyl-l-H-tetra2ol-5-yl-thio)-acetylthio7"l~ methoxyoxalyl-azetidin-2-one. 1.8 g of the compound prepared in Example 8 were dissolved .20 in 200 ml of dichloromethane and cooled to -78°C.

A flow of ozonized oxygen was bubbled through the solution until a blue colour appeared. A few drops of trimethylphosphite were added and the mixture was raised to room temperature. Removal of the solvent by evaporation gave 1.3 g of the title compound.

PMR (CDC13) δ 2.9-3.7 (>, 2 H, COCHgCH S); 3.85 (s, 3 H, COOCH3; 3.98 (s, 3 H, N-CH3>; 4.35 (s, H, CHgS); 5.75 (m, 1 H, CHjCH S).

EXAMPLE 10 46-((1-methyl-l-H-tetra2Ql-5-yl-thio)-acetylthio]-azetidin-2-one.

N·-N 1.2 g of the compound prepared in Example 9 were dissolved in a 1:1 by volume ethyl acetate:methanol mixture and a few grams of silica gel were added under vigorous stirring. After one hour the insoluble matter was filtered off and the solution was evaporated in vacuo. The title compound was crystallized from methanol:diethyl ether: 0.6 g were obtained.

EXAMPLE 11 .25 methyl 6-(1-hydroxyethyl)-3-penicillanate To a solution of 2.2 g of methyl penicillanate in 30 ml - 16 of anhydrous tetrahydrofuran, a slight excess of lithium diisopropylamide was added at -78°C under nitrogen. An excess of acetaldehyde was dropped in and the mixture was stirred for 5 minutes. The reaction was then quenched with a trace of acetic acid; the mixture was poured into water and extracted with dichloromethane. The organic layers were dried over anhydrous sodium sulphate and evaporated in vacuo to give 0.8 g of the title compound.

EXAMPLE 12 methyl 6-(1-p-nitrobenzyloxycarbonyloxyethyl)-3-penicillanate 1.2 g of methyl 6-(l-hydroxyethyl)-3-penieillanafee, prepared as described in Example 11, were dissolved in 40 ml of tetrahydrofuran cooled to -78eC and treated with one equivalent of butyl lithium. 1.2 equivalents f. of p-nitrobenzyloxycarbonyl chloride were added xo the mixture. After 30 minutes at -78°C, the reaction mixture was left at room temperature for 60 minutes, poured into water and extracted with dichloromethane. 1.4 g of the title compound were obtained after drying over anhydrous sodium sulphate and evaporating off the solvent.

EXAMPLE 13 γ. methyl-6-(l-p-nitrobenzyloxycarbonyloxyethyl-5— -penicillanate-S-oxide 409 - 17 0 1.8 g of methyl 6-[l-p-nitrobenzyloxycarbonyloxyethyl]-3-penicillanate, prepared as described in Example 12, were dissolved in 50 ml of dichloromethane and treated at 0°C with 1.5 equivalents of m-chloroperbenzoic acid. The organic phase was shaken with a saturated solution of sodium bicarbonate, extracted, dried over anhydrous sodium sulphate and evaporated: 1.4 g of the expected sulphoxide were obtained.

EXAMPLE 14 4B~(l-acetoxymethyl-3-acetoxy-l-propenylsulphinyl)-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-l-(l-methoxycarbonyl-2-methyl-allyl)-azetidin-2-one (3): R=CH3, R'=CH3CH.0 A solution of 2.0 g of the compound prepared in Example 13 and 2.4 g of butyndiol diacetate in 50 ml of toluene was refluxed for 24 hours. The trapped compound was then purified by silica gel column chromatography eluting with 9:1 by volume dichloromethane:ethyl acetate. 1.1 g of the title compound were obtained.

EXAMPLE 15 48-(l-acetoxymethyl-3-acetoxy-l-propenylsulphinvl)-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-(I-meth=xycarbonyl-2-methyl-l-propenyl)-azetidin-2-one - 18 (4): R=CH3, R'=CH3CH.O.C.OCH2 NOj, Y=CH2O.CO.CH3,Z=OCOCH3 1.3 g of the compound prepared in Example 14 were dissolved in 80 ml of dichloromethane. 0.3 ml of triethylamine were added and the mixture was left at room temperature for 2 hours. The title compound was obtained in pure form in quantitative yield by evaporating off the solvent.

EXAMPLE 16 48-(1-acetoxymethyl-3-acetoxy-l-propenylthio)-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-l-metboxycarbonyl-2-methyl-l-propenyl)-azetidin-2-one. 11 Γ\ (12 ) : R=CH3, R' =CH3CH. 0. C. 0CH2 1.5 g of the compound prepared in Example 15 were dissolved in 10 ml of anhydrous dimethylformamide and cooled to -20°C. 0.8 ml of phosphorus tribromide were added, and the mixture was stirred for 10 minutes. It was then diluted with ethyl acetate and washed twice with a saturated solution of sodium bicarbonate. The organic layer was dried over anhydrous sodium sulphate and evaporation off of the solvent gave 1.1 g of the title compound.

EXAMPLE 17 46~acetylglycolloylthio-3-(l-p-nitrobenzyloxycarbonyloxyethyl)-l-methoxyoxalyl-azetidin-2-one. 43409 - 19 ' /"λ (13) : R=CH3, R'=CH3CH.O.C.OCH2/ o\ NO2, Z-O.CO.CHj 1.4 g of the compound prepared in Example 16 in 120 ml of dichloromethane were cooled to -78°C. Ozone in oxygen was bubbled through the solution until a blue colour appeared. The solution was shaken with an aqueous solution of sodium pyrosulphite and dried over anhydrous sodium sulphate. Evaporation off of the solvent gave 0.8 g of the title compound.

EXAMPLE 18 46-acetylglycolloylthio-3-(l-p-nitrobenzyloxycarbonyloxyethyl)-azetidin-2-one • 10 11 * * * 15 * * * * 20 (14) : R'=CH3CH.O.C.OCH2 NOj, Z=O.CO.CH3 0.800 g of the compound prepared in Example 17 were dissolved in 50 ml of methanol and a few grams of silica gel were added. The mixture was left at room temperature for 60 minutes, and then the insoluble material was filtered off. The filtrate, after the solvent had been removed by evaporation, gave 0.300 g of the title compound.

Claims

1. A process for the preparation of an azetidinone derivative having the general fonnula I wherein R' is as herein defined and X represents a group of the formula CH 2 Z wherein Z is as herein defined, the process comprising condensing, in an inert solvent at elevated temperature, a penicillanic acid S-oxide ester of the general formula (2) as herein defined with an acetylenic compound of the general formula ZC^CsCY wherein Z is as herein defined, isomerizing the resultant compound of the general formula (3) as herein defined, reducing the 4(3-(substituted vinylsulphinyl) group of the resultant azetidinone derivative of the general formula (4) as herein defined by the action of a reducing agent, submitting the resultant azetidinone derivative of the general formula (12) as herein defined to ozonolysis in solution at reduced temperature whereby both carbon-carbon double bonds are converted to keto groups, and removing the 1-alkoxyoxalyl group from the resultant azetidinone derivative of the general formula (13) as herein defined by mild alkaline hydrolysis or by the action of silica gel. t

2. A process for the preparation of an azetidinone derivative having the general formula I wherein R' is as herein defined and X represents a group of the 4-9409 formula CHjZ' wherein Z' is as herein defined, the process being as defined in claim 1 with the additional step of converting the substituent 2 into a substituent Z' as herein defined, the additional step being carried out at any stage in the process after the condensation of the penicillanic acid S-oxide ester with the acetylenic compound.

3. A process according to claim 1 or claim 2 in which the isomerization is carried out in basic conditions.

4. A process according to any preceding claim in which the reducing agent is phosphorus tribromide or sodium iodide in acetyl chloride.

5. A process according to claim 1, the process being substantially as described herein with reference to Examples 14 to 18.

6. A process according to claim 2, the process being substantially as described herein with with reference to Examples 5 to 10.

7. An azetidinone derivative having the general formula I wherein R' represents a hydroxyaikyl group having from 1 to 4 carbon atoms, the alcoholic function of the hydroxyaikyl group being free or protected by a g-nitrobenzyloxycarbonyl group, and X represents a group of the formula CHjA wherein A is as herein defined.

8. 4f> -acetylglycolloylthio-3-(l-g-nitrobenzyloxycarbonyloxyethyl)-azetidin-2-one.